ABSTRACT
Cytestrole acetate (CA), in the structure of which the steroidal antiestrogen component is associated with bis-ß-cloroethylamino group, exhibits a strong cytotoxic activity against hormone-dependent cancer cell lines (CaOV, HeLa, MCF-7). In doxorubicin-resistant MCF-7 cells, CA potentiates the cytotoxic effect of etoposide and doxorubicin, and the IC50 for CA in these cells is 40 times lower than that for tamoxifen (TAM). In transplantable mice breast adenocarcinoma Ca-755, the therapeutic CA dose is 25 mg/kg when administered subcutaneously in oil solution for 5 days. On the DMBA-induced mammary tumors in rats, CA injected subcutaneously led to partial regressions 4 weeks after treatment in 75% of test rats, whereas TAM produced this effect in 43% of rats. Among various drug forms of CA, the most active were oil solution of CA in gelatin capsules for oral use and liposomal emulsion for intravenous administration, since these forms exhibited the highest values of Ca-755 tumor growth inhibition index (TGI = 97 - 98%).
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents, Hormonal/pharmacology , Breast Neoplasms/drug therapy , Cytostatic Agents/pharmacology , Estrogen Antagonists/pharmacology , Ethinyl Estradiol/analogs & derivatives , Adenocarcinoma/pathology , Animals , Breast Neoplasms/pathology , Cell Line, Tumor , Doxorubicin/pharmacology , Drug Administration Schedule , Drug Synergism , Ethinyl Estradiol/pharmacology , Etoposide/pharmacology , Female , Humans , Inhibitory Concentration 50 , Injections, Subcutaneous , Mice , Rats , Tamoxifen/pharmacology , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Esterification of 3-hydroxyl group in 11-acyloxyestra-1,3,5(10)-trienes with p-[bis(2-chloroethyl)amino]phenylacetic acid led to antitumor steroids displaying antiestrogenic and cytotoxic activities. Our substances exhibit their activities on the model of murine mammary adenocarcinoma Ca-755, with inhibition of the tumor growth being 94-99%. A new approach was used for the 11alpha-hydroxylation of estra-1,3,5(10)-trienes.
Subject(s)
Antineoplastic Agents/pharmacology , Estrenes/pharmacology , Estrogen Antagonists/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Drug Screening Assays, Antitumor , Estrenes/chemical synthesis , Estrogen Antagonists/chemical synthesis , Female , Humans , Mammary Neoplasms, Experimental/drug therapy , Mice , Neoplasms, Hormone-Dependent , Ovarian NeoplasmsABSTRACT
The cytotoxic activity of complexes of hydrolysable tannins of Chamaenerium angustifolium L. Scop. and Hippophae rhamnoides L. was compared with that of the antineoplastic drugs vinoblastin (VLB), methotrexate (MT), and 5-fluorouracil (5-FU). The tannins yield to VLB and MT in activity but resemble 5-Fu in their active concentration. They inhibited succinate oxidation by the rat liver mitochondria and their cytotoxicity was displayed in much lower concentrations than their inhibitory effect on mitochondrial respiration. It is concluded that tannins inhibit the respiratory chain at the third point of conjugation in the transfer of electrons from cytochrome c to oxygen.
Subject(s)
Antineoplastic Agents/toxicity , Mitochondria, Liver/drug effects , Tannins/toxicity , Animals , Antimetabolites, Antineoplastic/toxicity , Antineoplastic Agents/pharmacology , Antineoplastic Agents, Phytogenic/toxicity , Burkitt Lymphoma , Dose-Response Relationship, Drug , Fluorouracil/toxicity , Lymphocytes/drug effects , Male , Methotrexate/toxicity , Mitochondria, Liver/metabolism , Oxygen Consumption/drug effects , Rats , Rats, Wistar , Tannins/pharmacology , Tumor Cells, Cultured , Vinblastine/toxicityABSTRACT
The immunopharmacology and pharmacokinetics of synthetic beta-carotene were studied in complex clinico-laboratory investigations after single and repeated per os administrations of various doses of the drug to healthy volunteers and cancer patients. Repeated treatment with beta-carotene at a dose of 30 mg caused no significant changes in the immunological parameters studied. However, treatment with a dose of 250 mg altered the parameters as follows: alteration of beta-carotene content in blood, elevation of the counts of lymphocytes and T lymphocytes forming "active" rosettes, increase in the proliferative response of lymphocytes to the mitogen PWM and activation of natural killers. Single administration of the drug in a dose of 1,000 and 2,000 mg led to short-term reversible immunodepression, appeared as leukopenia, abolition of the proliferative response of lymphocytes to mitogens and inhibition of T suppressors. Kinetics of retinoids and beta-carotene content in blood plasma was studied after single per os administration of drug megadoses.
Subject(s)
Carotenoids/pharmacokinetics , T-Lymphocytes/immunology , Adult , Carotenoids/pharmacology , Carotenoids/therapeutic use , Cell Division/drug effects , Female , Humans , Male , Middle Aged , Neoplasms/drug therapy , Neoplasms/immunology , Rosette Formation , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , beta CaroteneABSTRACT
An acyclic analogue of 9-deazainosine, 9-(2-hydroxyethoxymethyl)-9-deazahypoxanthine, and related compounds have been synthesized starting from 9-(hydroxyethyl)-9-deazahypoxanthine. The acyclo-9-deazainosine exhibited some cytotoxic activity.
Subject(s)
Inosine/analogs & derivatives , Antineoplastic Agents , Antiviral Agents , Cell Division/drug effects , Cells, Cultured , Chemical Phenomena , Chemistry , Female , Humans , Inosine/chemical synthesis , Inosine/pharmacology , Ovarian Neoplasms/pathology , Simplexvirus/drug effects , Structure-Activity RelationshipABSTRACT
Differentiation to reflexes with defensive reinforcement is elaborated in deprived rats more readily and is more pronounced than to those with drinking reinforcement. This is also confirmed in other experimental series: with a transfer to reinforcement of both positive and differentiation signals, with reversal of their significance, with a stochastic stereotype, with drawing closer the pitch of the differentiation and positive tones. In a stereotype of alternating positive reflexes with drinking reinforcement and of their differentiations, the animals' reactions are predominantly linked to the alternation of signals, while in the case of defensive reinforcement they are linked to the acoustic signals.
